The effect of age on digoxin pharmacokinetics in Fischer-344 rats.
Digoxin protein binding and pharmacokinetics were studied in 4-, 14-, and 25-month-old male Fischer-344 rats to determine if there were age-dependent changes in digoxin disposition. Serum protein binding did not differ among age groups. The average percentage unbound digoxin for all animals was 61.3 +/- 5.3% (means +/- SD, n = 15). For pharmacokinetic studies, [3H]digoxin and 1 mg/kg unlabeled digoxin were administered as an intravenous bolus dose to animals from each age group. The [3H]digoxin terminal elimination half-life was 2.0, 2.3, and 2.5 hr, respectively. The steady-state volume of distribution in the three age groups was 1.51, 1.49, and 1.27 liters/kg, respectively. Total body clearance for the three age groups was 14.2, 12.1, and 7.5 ml/min/kg, respectively. Analysis of variance of these data followed by Duncan's multiple range test indicated a significant decrease in clearance in the aged rats (25-month-old, p less than 0.05). This age-dependent decrease in clearance suggested that digoxin pharmacokinetics could be a significant factor in age-related alterations in digoxin cardiotoxicity in the rat, as it is in humans, and that the Fischer-344 rat could be a useful model for studies of digoxin pharmacokinetic changes with age.
Evans
R L
RL
Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock 72205.
Owens
S M
SM
Ruch
S
S
Kennedy
R H
RH
Seifen
E
E
D000375:Aging / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D001798:Blood Proteins / Q000187:drug effects / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004077:Digoxin / Q000097:blood / Q000493:pharmacokinetics*; D007275:Injections, Intravenous; D008297:Male; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D011916:Rats, Inbred F344 / Q000378:metabolism*; D011919:Rats, Inbred Strains / Q000378:metabolism*; D014316:Tritium
D001798:Blood Proteins; D014316:Tritium; D004077:Digoxin